The identification and cloning of tumor associated antigens (TAA) has led to vaccination strategies designed to elicit anti-tumor immune responses resulting in host rejection of their tumor. These strategies include vaccination with antigenic peptides alone or with cytokines, recombinant vaccinia or adenoviruses encoding TAA genes, and peptide loaded dendritic cells. Despite overwhelming evidence of successful vaccination against several melanoma TAA=s, few objective clinical responses have been observed. In animal models, effective treatment correlates with vaccines that elicit high avidity t cells. The lack of clinical responses could be due to failure to elicit immune effectors with sufficient avidity to mediate tumor regression. We have reported that the T cell receptor (TCR) repertoire used by MART-1:27-35 and gp100:209-217 reactive T cell clones is quite diverse. This diversity leads to differences in how T cells recognize antigen which in turn can influence T cell avidity. Therefore, the ability to select high avidity T cells based on their TCR might lead to more effective therapeutic cells. Alternatively, we have reported using TCR genes to redirect the specificity of normal PBL- derived T cells to recognize melanoma cell lines. Using a retroviral gene transfer system, both CD4+ and CD8+ T cells could be redirected to recognize MART-1:27-35 peptide loaded cells and CD8+ T cells could recognize HLA-A2+, MART-1+ tumor cells. Although this TCR could generate MHC class I restricted helper T cells, its dependence on CD* meant it was unable to transfer tumor cell reactivity to the CD4+ T cells. The objective of this proposal is to determine which functions of the C8 coreceptor are required for efficient tumor cell recognition. Based on this knowledge, it might be possible to isolate or engineer TCR=s which do not require CD8 for tumor cell recognition. These CD8 independent TCR=s may not only permit us to engineer CD4+ T cells to provide MHC class I restricted T cell help, they may produce CD8+ T cells with enhanced avidity resulting in greater anti-tumor effector function.